The waters of the “red tide” are awash with noxious agents, the most infamous of which are the paralytic shellfish poisons (PSP) (Seafood and Freshwater Toxins: Pharmacology, Physiology, and Detection; Botana, L. M., Ed.; Marcel Dekker: New York, 2000.) Small molecule, bis-guanidinium structures—saxitoxin, neosaxitoxin, and the gonyautoxins—unique in both their form and function, represent the principle constituents of PSP's. (For leading reviews, see: (a) Llewellyn, L. E. Nat. Prod. Rep. 2006, 23, 200-222. (b) Hall, S.; Strichartz, G.; Moczydlowski, E.; Ravindran, A.; Reichardt, P. B. ACS Symp. Series 1990, 418, 29-65.) These highly polar, heteroatom-rich compounds are exquisitely designed corks that act to stopper ion flux through voltage-gated Na+ channels (Nav), thus inhibiting electrical conduction in cells. (see, e.g., Tetrodotoxin, Saxitoxin, and the Molecular Biology of the Sodium Channel; Eds. C. Y. Kao; S. R. Levinson; Ann. New York Acad. Sci.: New York, Vol 479, 1986; Tikhonov, D. B.; Zhorov, B. S. Biophys. J. 2005, 88, 184-197, and references therein.)
The intricate molecular shape common to these toxins coupled with their importance as pharmacological tools for ion channel study have inspired efforts aimed at their de novo assembly. Three prior works have described preparations of saxitoxin (STX) and one a decarbamoyloxy form. ((See, e.g., (a) Tamino, H.; Nakata, T.; Kaneko, T.; Kishi, Y. J. Am. Chem. Soc. 1977, 99, 2818-2819. (b) Kishi, Y. Heterocycles 1980, 14, 1477-1495. (c) Jacobi, P. A.; Martinelli, M. J.; Polanc, S. J. Am. Chem. Soc. 1984, 106, 5594-5598. (d) Martinelli, M. J.; Brownstein, A. D.; Jacobi, P. A.; Polanc, S. Croat. Chem. Acta 1986, 59, 267-295. (e) Fleming, J. J.; Du Bois, J. J. Am. Chem. Soc. 2006, 128, 3926-3927. (f) Fleming, J. J.; McReynolds, M. D.; Du Bois, J. J. Am. Chem. Soc. 2007, 129, 9964-9975. Following their earlier report, Kishi et al have described an asymmetric synthesis of (−)-decarbamoylsaxitoxin, see: Hong, C. Y.; Kishi, Y. J. Am. Chem. Soc. 1992, 114, 7001-7006. See also, e.g., Iwamoto, O.; Koshino, H.; Hashizume, D.; Nagasawa, K. Angew. Chem. Int. Ed. 2007, 46, 8625-8628.)
Pain sensations include sharp pain, dull pain, ache, and other forms of pain sensations. Pain is a sensation that may be of varying intensity and duration, and may result from a variety of causes. For example, pain may be acute, e.g., as a result of injury, illness or trauma; may be chronic, e.g., as a result of a chronic disease or condition, inflammation, cancer, or other cause; may be localized or diffuse; may be of low intensity, or of moderate intensity, or of high intensity. Thus, pain is a varied sensation, which includes, for example, acute pain, chronic pain, visceral pain, surgical pain, joint pain, bone pain, back pain, headache pain, neurogenic pain, phantom-limb pain, and other forms and experiences of pain. However, in general, whatever the intensity or duration, and whatever the cause, people prefer to lessen or eliminate the pain sensation, wherever possible.
Pain can often be alleviated by the administration of pharmaceuticals to a subject. One mechanism of alleviating pain sensation is to block the transmission of nerve signals, as, for example, by blocking conduction of nerve impulses along nerve fibers. For example, such impulses can be blocked by reducing, blocking, or altering the action of sodium channels. Sodium channels can be affected by compounds such as saxitoxin, gonyautoxin, zetekitoxin, and other molecules known as “site one sodium channel blockers” (see, e.g., Llewellyn, Nat. Prod. Rep. 23: 200-222 (2006)). However, as suggested by the term “toxin” in their names, such molecules may also have effects in addition to blocking pain sensation. Thus, identification of molecules which are effective to alleviate the sensation of pain, without dangerous side effects, is desired.
Chronic pain is a major, universal health problem and one of the most common reasons that people seek medical care. “Why am I in (chronic) pain?” “What's causing my pain?” or “Where is the pain coming from?” are some of the tough questions that individuals suffering from chronic pain often struggle with to get answers. The paucity of objective, diagnostic tests and a limited armamentarium of effective and safe medicines no doubt fuel the aggravation shared by chronic pain sufferers and their caregivers. Current methods used to diagnose a patient's pain are highly subjective and rely on patient self-reporting. Individuals suffering from chronic pain endure a number of tests and are often relegated to empiric analgesic testing and surgical procedures with limited objective basis for such treatments. Additionally, currently used state-of-the-art medical imaging technologies such as x-rays, computed tomography (CT), ultrasound, and conventional magnetic resonance imaging (MRI), have been inadequate in the assessment of chronic pain syndromes because they rely heavily upon anatomic abnormalities. Significant intervertebral disc abnormalities using conventional MRI, for example, can be found in 27-31% asymptomatic subjects. Additionally, the natural progression of degenerative disc disease in individuals does not correlate with development of pain symptomology, and provocative discography and MR-based morphometric measurements have only weak association with back pain episodes. More recently, meniscal tears as detected on MRI have been found to be nearly equally prevalent (˜60%) in symptomatic and asymptomatic knees of middle aged and elderly persons, again, underscoring the poor relationship between MR findings and pain causation. Yet, despite such evidence to the contrary, the use of such anatomy-based imaging findings unfortunately remains an important part of the treatment algorithm for a wide range of diseases! As a result, a large number of patients are subject to unnecessary surgeries and inadequate treatments.